同: PFIC

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gradually advancing in extent
a tense of verbs used in describing action that is on-going (同)progressive tense, imperfect, imperfect tense, continuous tense
favoring or promoting reform (often by government action) (同)reformist, reform-minded
(of a card game or a dance) involving a series of sections for which the participants successively change place or relative position; "progressive euchre"; "progressive tournaments"
(of taxes) adjusted so that the rate increases as the amount of income increases
advancing in severity; "progressive paralysis"
favoring or promoting progress; "progressive schools"
relating to or having the characteristics of a family; "children of the same familial background"; "familial aggregation"
occurring among members of a family usually by heredity; "an inherited disease"; "familial traits"; "genetically transmitted features" (同)genetic, hereditary, inherited, transmitted, transmissible

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(行列などが)『前進する』,進んで行く / (事態が)進展する,進行する / 『進歩的な』,革新的な / (病気・暴力などが)次第に悪くなる(広がる) / (課税が)累進的な / (文法で)進行[形]の / 進歩的な人,革新主義者
家族の,家族特有の / 違伝的な,血統にあらわれる

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/01/16 15:43:44」(JST)

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Progressive familial intrahepatic cholestasis (PFIC) refers to a group of familial cholestatic conditions caused by defects in biliary epithelial transporters. The clinical presentation usually occurs first in childhood with progressive cholestasis. This usually leads to failure to thrive, cirrhosis, and the need for liver transplantation.

Signs and symptoms

The onset of the disease is usually before age 2, but patients have been diagnosed with PFIC even into adolescence. Of the three entities, PFIC-3 usually presents earliest. Patients usually present in early childhood with cholestasis, jaundice, and failure to thrive. Intense pruritus is characteristic;^[1] in patients who present in adolescence, it has been linked with suicide. Patients may have fat malabsorption, leading to fat soluble vitamin deficiency, and complications, including osteopenia.^[2]

Pathogenesis

Progressive familial intrahepatic cholestasis is inherited in an autosomal recessive pattern.

PFIC-1 is caused by a variety of mutations in ATP8B1, a gene coding for a P-type ATPase protein, FIC-1, that is responsible for phospholipid translocation across membranes.^[3] It was previously identified as clinical entities known as Byler's disease and Greenland-Eskimo familial cholestasis. Patients with PFIC-1 may also have watery diarrhea, in addition to the clinical features below, due to FIC-1's expression in the intestine. How ATP8B1 mutation leads to cholestasis is not yet well understood.

PFIC-2 is caused by a variety of mutations in ABCB11, the gene that codes for the bile salt export pump, or BSEP. Retention of bile salts within hepatocytes, which are the only cell type to express BSEP, causes hepatocellular damage and cholestasis.

PFIC-3 is caused by a variety of mutations in ABCB4, the gene encoding multidrug resistance protein 3 (MDR3),^[4] which codes for a floppase responsible for phosphatidylcholine translocation. The defective phosphatidylcholine translocation leads to a lack of phosphatidylcholine in bile. Phosphatidylcholine normally chaperones bile acids, preventing damage to the biliary epithelium. The free or "unchaperoned" bile acids in bile of patients with MDR3 deficiency cause a cholangitis. Biochemically, this is of note, as PFIC-3 is associated with a markedly elevated GGT.

The inheritance pattern of all three forms of PFIC defined to date is autosomal recessive.

Liver biopsies typically show evidence of cholestasis (including bile plugs and bile infarcts), duct hypoplasia, hepatocellular injury, and Zone 3 fibrosis. Giant cell change and other features of hepatocellular injury are more pronounced in PFIC-2 than in PFIC-1 or PFIC-3. End-stage disease in all forms of PFIC defined to date is characterized by bridging fibrosis with duct proliferation in peri-portal regions.^[5]

Diagnosis

Biochemical markers include a normal GGT for PFIC-1 and -2, with a markedly elevated GGT for PFIC-3. Serum bile acid levels are grossly elevated. Serum cholesterol levels are typically not elevated, as is seen usually in cholestasis, as the pathology is due to a transporter as opposed to an anatomical problem with biliary cells.

Treatment

Initial treatment is supportive, with the use of agents to treat cholestasis and pruritus, including the following:

Ursodeoxycholic acid
Cholestyramine
Rifampin
Naloxone, in refractory cases

Patients should be supplemented with fat-soluble vitamins, and occasionally medium-chain triglycerides in order to improve growth.

When liver synthetic dysfunction is significant, patients should be listed for transplantation. Family members should be tested for PFIC mutations, in order to determine risk of transmission.

Prognosis

The disease is typically progressive, leading to fulminant liver failure and death in childhood, in the absence of liver transplantation. Hepatocellular carcinoma may develop in PFIC-2 at a very early age; even toddlers have been affected.

Epidemiology

Consanguinity is believed to be a major risk factor.
Similar transport protein mutations are believed to pose a higher risk for intrahepatic cholestasis of pregnancy.

References

^ Shneider BL (2004). "Progressive intrahepatic cholestasis: mechanisms, diagnosis and therapy". Pediatric transplantation 8 (6): 609–12. doi:10.1111/j.1399-3046.2004.00240.x. PMID 15598335.
^ "eMedicine - Progressive Familial Intrahepatic Cholestasis : Article by Karan M Emerick, MD". Retrieved 2007-07-21.
^ Bull LN, van Eijk MJ, Pawlikowska L, et al. (1998). "A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis". Nat. Genet. 18 (3): 219–24. doi:10.1038/ng0398-219. PMID 9500542.
^ Jacquemin E, De Vree JM, Cresteil D, et al. (2001). "The wide spectrum of multidrug resistance 3 deficiency: from neonatal cholestasis to cirrhosis of adulthood". Gastroenterology 120 (6): 1448–58. doi:10.1053/gast.2001.23984. PMID 11313315.
^ Alonso EM, Snover DC, Montag A, Freese DK, Whitington PF (1994). "Histologic pathology of the liver in progressive familial intrahepatic cholestasis". J. Pediatr. Gastroenterol. Nutr. 18 (2): 128–33. doi:10.1097/00005176-199402000-00002. PMID 8014759.

External links

Patient pamphlet
GeneReview/NIH/UW entry on Low γ-GT Familial Intrahepatic Cholestasis
OMIM entry on CHOLESTASIS, PROGRESSIVE FAMILIAL INTRAHEPATIC, 1; PFIC1

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. 抱合型高ビリルビン血症関連の遺伝性疾患 inherited disorders associated with conjugated hyperbilirubinemia
2. 新生児胆汁うっ滞の原因 causes of neonatal cholestasis
3. 肝内胆管の消失および胆管消失症候群 hepatic ductopenia and vanishing bile duct syndrome
4. 新生児胆汁うっ滞に対するアプローチ approach to neonatal cholestasis
5. 黄疸または無症候性高ビリルビン血症の分類および原因 classification and causes of jaundice or asymptomatic hyperbilirubinemia

English Journal

Biosynthesis and trafficking of the bile salt export pump, BSEP: Therapeutic implications of BSEP mutations.

Soroka CJ1, Boyer JL2.
Molecular aspects of medicine.Mol Aspects Med.2014 Jun;37:3-14. doi: 10.1016/j.mam.2013.05.001. Epub 2013 May 15.
The bile salt export pump (BSEP, ABCB11) is the primary transporter of bile acids from the hepatocyte to the biliary system. This rate-limiting step in bile formation is essential to the formation of bile salt dependent bile flow, the enterohepatic circulation of bile acids, and the digestion of die
PMID 23685087

Complications Following Liver Transplantation for Progressive Familial Intrahepatic Cholestasis.

Berumen J1, Feinberg E, Todo T, Bonham CA, Concepcion W, Esquivel C.
Digestive diseases and sciences.Dig Dis Sci.2014 May 31. [Epub ahead of print]
PMID 24879297

Molecular mechanistic explanation for the spectrum of cholestatic disease caused by the S320F variant of ABCB4.

Andress EJ1, Nicolaou M, Romero MR, Naik S, Dixon PH, Williamson C, Linton KJ.
Hepatology (Baltimore, Md.).Hepatology.2014 May;59(5):1921-31. doi: 10.1002/hep.26970. Epub 2014 Apr 1.
ABCB4 flops phosphatidylcholine into the bile canaliculus to protect the biliary tree from the detergent activity of bile salts. Homozygous-null ABCB4 mutations cause the childhood liver disease, progressive familial intrahepatic cholestasis, but cause and effect is less clear, with many missense mu
PMID 24806754

Japanese Journal

細胞膜を介したトランスポーター介在性輸送と小胞輸送によるその制御

膜 40(1), 21-28, 2015
NAID 130005069456

Phospholipid flippase activities and substrate specificities of human type IV P-type ATPases localized to the plasma membrane.

The Journal of biological chemistry 289(48), 33543-33556, 2014-11-28
NAID 120005690224

トランスポーター関連疾患に対する新規治療戦略の開発を指向した創薬研究

YAKUGAKU ZASSHI 134(10), 1007-1011, 2014
NAID 130004693883

Related Pictures

★リンクテーブル★

リンク元	「PFIC」
関連記事	「intrahepatic cholestasis」「familial」「progressive」「intrahepatic」

「PFIC」

Progressive familial intrahepatic cholestasis
Classification and external resources
OMIM	211600 601847 602347
DiseasesDB	29084
eMedicine	ped/2771
GeneReviews	Low γ-GT Familial Intrahepatic Cholestasis;
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